Citations

ABSTRACT Objectives To characterize practice patterns and outcomes in the management of low‐ and intermediate‐grade salivary gland carcinoma prior to the existence of treatment guidelines. Methods Analysis of a registry of patients who underwent parotid and submandibular gland resections for low‐and intermediate‐grade carcinomas between 2010 and 2019. Results Of all 786 patients included in the study, 726 (92%) had preoperative imaging and 653 (83%) had preoperative biopsy. Of the 729 patients with parotid gland cancer, the majority underwent superficial ( n = 384, 53%) or total ( n = 254, 35%) parotidectomy. In patients with facial nerve preservation, total parotidectomy was associated with a significant increase in transient facial weakness (72/177 (41%) vs. 82/311 (26%), RR 0.65, 95% CI 0.50–0.84, p < 0.05) and permanent facial nerve weakness (23/176 (13%) vs. 16/301 (5%), RR 0.41, 95% CI 0.22–0.75, p < 0.05) compared to superficial parotidectomy. Adjuvant radiation therapy ( RT ) was delivered to 285 (36%) patients. The proportion of patients receiving adjuvant RT declined significantly over the time period from 2015 to 2019 compared to 2010 to 2014 at 162/504 (32%) and 123/282 (44%), respectively ( RR 0.74, 95% CI 0.61–0.89, p < 0.05). When comparing the time periods from 2015 to 2019 and 2010 to 2014, there was no significant difference in local control rates ( RR 0.52, 95% CI 0.26–1.04, p = 0.06) or regional control rates ( RR 0.75, 95% CI 0.26–2.13, p = 0.58). Conclusions Management of low‐ and intermediate‐grade salivary cancer from 2010 to 2019 was variable, which is expected given the rarity and heterogeneity of the disease and the lack of treatment guidelines prior to 2021. Most patients with parotid malignancies underwent superficial or total parotidectomy. The extent of parotidectomy had an impact on facial nerve function outcomes. Delivery of adjuvant radiation trended down with time. The data presented here will support dissemination of the guidelines and provide data that could inform future trials. Level of Evidence 2b.

ABSTRACT Aims X‐linked McLeod neuroacanthocytosis syndrome (MLS) is a rare neurodegenerative disorder characterised by the presence of red blood cell acanthocytosis and a chorea syndrome. Analogous to Huntington's disease (HD), MLS displays cognitive and behavioural symptoms besides the progressive movement disorder. This study aimed to describe the neuropathology of MLS in the largest case series to date. Methods Clinical data were collected, and neuropathological assessments were performed on eight male MLS patients originating from Finland, New Zealand, Switzerland, Scotland and the United States. Results Macroscopic data were available from six patients, with five showing atrophy of the basal ganglia, which was more pronounced in the caudate nucleus and to a lesser extent in the putamen and pallidum. Histology revealed neuronal loss and accompanying gliosis in the basal ganglia of all patients. The extent of these alterations varied widely, with a decreasing gradient of severity from the caudate nucleus to the putamen and the pallidum, mirroring the macroscopic findings. In addition, we detected intraneuronal vacuoles in the striatum in half of the patients. Conclusions MLS neuropathology is characterised macroscopically by atrophy and microscopically by neuronal loss and gliosis of the basal ganglia, with a decreasing gradient of severity from the caudate nucleus, the putamen to the pallidum. Analogous to the grading system for HD, we propose a neuropathological grading system for MLS based on the current observations in the largest MLS cohort examined to date. Standardised criteria are crucial for neuropathological assessment of this extremely rare disease.

Abstract Hereditary adult-onset ataxias are a heterogeneous group of phenotypically overlapping conditions, often caused by pathogenic expansions of short tandem repeats. Currently, 18 repeat disorders with a core phenotype of adult-onset ataxia are known. Diagnosis typically relies on sequential PCR-based methods, which are labour-intensive and lack precision. Long-read sequencing (LRS) has the potential to overcome these limitations and is currently implemented and validated in clinical genetics. Using clinical nanopore Cas9-targeted sequencing (Clin-CATS) for parallel in-depth repeat analysis, we evaluated a diagnostic cohort of 513 adult-onset ataxia patients, determining frequencies of all known repeat-associated ataxias except Spinocerebellar ataxia 4 (SCA4), as well as the carrier frequencies for autosomal-recessive disorders, RFC1 spectrum disorder and Friedreich’s ataxia (FRDA). Additionally, phenotypes of patients with established genetic diagnoses were characterized, especially those of patients living with RFC1 spectrum disorder and SCA27B. Repeat-associated ataxias were confirmed in 33.3% of cases, including rare ataxias, such as SCA10, SCA36 and SCA37, alongside as the most prevalent conditions SCA27B and RFC1 spectrum disorder. Potentially pathogenic expansions in FGF14 were identified in an additional 4.7% of patients. Testing of another 347 patients for ZFHX3 expansions linked to SCA4 did not identify any cases. Dual diagnoses were frequent, occurring in 6.4% of patients with repeat-associated ataxia. We confirmed a high RFC1 spectrum disorder carrier frequency (7.2%) and reclassified certain FXN expansions as likely non-pathogenic, resulting in a lower than estimated carrier frequency for FRDA of 0.8%. We also identified novel repeat configurations in several loci and illustrated the high heterogeneity of repeat expansions in RFC1, highlighting it as a potential source of false results when using PCR-based methods. This study underscores the diagnostic advantages of LRS for comprehensive repeat analysis and recommends its adoption as a standard in clinical genetics, replacing Southern blot and PCR-based approaches. Furthermore, based on our findings in a large patient cohort a re-evaluation of existing phenotype-genotype correlations is recommended as well as evaluating additional parameters alongside the repeat length to improve diagnostic precision of repeat analysis.

ABSTRACT Aims The impact of treatment for tricuspid regurgitation (TR) across different levels of left ventricular ejection fraction (LVEF) remains uncertain. This study aimed to compare the outcomes of surgical and transcatheter tricuspid valve interventions (TTVI) to conservative (medical) management across LVEF categories. Methods and results Patients with severe isolated TR from the TRIGISTRY, a multicentre international registry, were categorized based on LVEF (preserved ejection fraction [pEF]: ≥50%, mildly reduced ejection fraction [mrEF]: 41–49%, and reduced ejection fraction [rEF]: ≤40%). We assessed the impact of treatment modality and procedural success (mild-to-moderate or lower residual TR) on 2-year survival within each LVEF category. Among 2384 patients, 1383 had pEF, 400 had mrEF, and 601 had rEF. Compared to conservative management, surgery (p &lt; 0.0005) and TTVI (p &lt; 0.0001) were associated with a survival benefit in patients with pEF. No significant survival advantage was observed in patients with mrEF (p = 0.28 for both), nor in those with rEF (p = 0.76 and p = 0.22, respectively). Similar results were obtained when surgical and transcatheter interventions were grouped (p &lt; 0.0001, p = 0.17 and p = 0.29 in patients with pEF, mrEF and rEF, respectively). Patients with residual TR after TTVI exhibited a trend toward worse survival compared to those managed conservatively across all LVEF categories (p = 0.47, p = 0.33 and p = 0.008 in pEF, mrEF and rEF, respectively). Conclusions Transcatheter tricuspid valve intervention, whether surgical or transcatheter-based, was associated with improved survival in patients with pEF but not in those with mrEF or rEF. Residual TR remained a significant prognostic factor across the entire LVEF spectrum. These findings highlight the need for careful patient selection when considering TTVI in individuals with rEF.

Background and objectives Arteriovenous malformations (AVMs) with perinidal aneurysms and single draining vein are associated with an elevated risk of rupture and increased procedural complexity. The role of preoperative embolization in this high-risk anatomical subset remains unclear. This study aimed to evaluate the safety and efficacy of microsurgery with preoperative embolization, compared with microsurgery alone in patients with such AVMs. Methods We conducted a multicenter retrospective analysis of an AVM registry from the MISTA (Multicenter International Study for Treatment of Brain AVMs) consortium and included AVMs with perinidal aneurysms and a single draining vein. Baseline characteristics, angiographic outcomes, functional outcomes, and complication rates were compared. Propensity score weighting (PSW) using the covariate balancing method was applied to adjust for baseline differences. Results Out of a total of 1919 patients, 65 met the inclusion criteria; 45 patients underwent preoperative embolization followed by microsurgery, and 20 underwent microsurgery alone. After adjustment, complete obliteration rates were similar between groups (OR 0.87, 95% CI 0.04 to 16.33, P=0.92), as were rates of functional independence at discharge and follow-up. Overall complication, symptomatic complication, and mortality rates did not differ significantly between groups. However, permanent complications were significantly lower in patients with preoperative embolization (OR 0.06, 95% CI 0.004 to 0.84, P=0.03). Discussion In patients with AVMs featuring perinidal aneurysms and single draining vein, preoperative embolization followed by microsurgery was associated with fewer permanent complications and no increase in adverse outcomes compared with microsurgery alone. However, given the small number of events, this finding should be interpreted cautiously.

Abstract Background and Aims The TRISCEND II trial demonstrated superior clinical benefits for patients with ≥severe tricuspid regurgitation (TR) treated with the EVOQUE transcatheter tricuspid valve replacement (TTVR) system plus medical therapy vs medical therapy alone. This work reports 1-year and 18-month outcomes in patients stratified by baseline TR severity. Methods The multicentre, prospective TRISCEND II trial enrolled 400 patients with symptomatic, ≥severe TR, and randomized 2:1 to TTVR (n = 267) or control (n = 133). In a post hoc analysis, patients were stratified into severe TR (n = 172) and massive/torrential TR (n = 220) cohorts. Clinical and quality-of-life outcomes were reported at 1 year, with Kaplan–Meier estimates for all-cause mortality and heart failure (HF) hospitalization assessed at 18 months. Study oversight included an independent echocardiographic core laboratory, clinical events committee, and data safety monitoring board. Results One year after TTVR, TR was ≤mild in 95.2% of severe TR and 95.3% of massive/torrential TR patients. The primary safety and effectiveness endpoint (win ratio) favoured TTVR over control regardless of baseline TR severity: severe {1.64 [95% confidence interval (CI): 1.11, 2.43]} and massive/torrential [2.20 (1.55, 3.14)]. At 18 months, TTVR patients had similar mortality to controls [rate difference: severe 0.2% (−11.6, 11.9), massive/torrential −5.8% (−17.6, 6.0)], whereas HF hospitalization rates favoured TTVR in the massive/torrential cohort [vs control, severe 9.8% (−3.0, 22.7), massive/torrential -15.2% (−28.9, −1.5)]. Conclusions Patients with ≥severe TR benefit from TTVR, experiencing improvements in TR severity, functional capacity, and quality of life regardless of baseline TR severity, with a signal for greater benefit in patients with more advanced disease.

Abstract Aims Aortic valve-sparing root replacement is recommended over composite root replacement for aortic root aneurysms, especially in younger patients, but long-term outcomes in low-volume nationwide settings remain unclear. The objectives are to compare long-term survival, stroke, and reoperation rates between the two procedures in a low-volume national setting. Methods and results Patients were identified from the Western Danish Heart Registry and the Danish Heart Registry. Cases were validated by review of operative descriptions. The primary outcome was long-term survival from all-cause mortality; secondary outcomes included stroke, reoperation, recurrent aortic regurgitation, and aortic stenosis. Groups were balanced using propensity score matching. Echocardiographic data were provided for the matched cohort. We identified 760 patients treated with composite root replacement and 179 patients with aortic valve-sparing root replacement between January 2010 and April 2022. Mean follow-up was 6.5 years. Composite root replacement patients were younger [50.7 years (SD 14.1) vs. 55.2 (SD 13.5), P &lt; 0.001], but more comorbid with a median EuroSCOREII of 5.5 [interquartile range (IQR): 3.3–11.7] vs. 3.4 (IQR: 2.6–5.0) (P &lt; 0.001). After matching 157 patients per group, aortic valve-sparing root replacement showed improved 10-year survival [91.2%, 95% confidence interval (CI) 82.3–95.8 vs. 80.4%, 95% CI 70.0–87.5, log-rank P = 0.026], with lower 10-year stroke risk (4.9%, 95% CI 1.8–13.0 vs. 18.9%, 95% CI 11.7–29.9, log-rank P = 0.007). Risk of reoperation was nonsignificant (log-rank P = 0.12), which was consistent in the crude population when accounting for competing risk of death (log-rank P = 0.09). Conclusion In this nationwide study, aortic valve-sparing root replacement was associated with better long-term survival and lower stroke risk, supporting its role as a durable surgical option for selected patients.

ABSTRACT Post‐translational modifications, such as glycosylation and phosphorylation, play a critical role in protein trafficking, interactions, and stability. Disruptions in these pathways can lead to glycosylphosphatidylinositol (GPI) deficiencies, which present with a spectrum of clinical features, including congenital anomalies, dysmorphic features, developmental delay, hypotonia, and epilepsy. Biallelic variants in PIGV , a key mannosyltransferase in GPI biosynthesis, cause Hyperphosphatasia with Impaired Intellectual Development Syndrome 1 (HPMRS1), a rare disorder characterized by hyperphosphatasia, seizures, developmental delay, hypotonia, abnormal MRI findings, and distinct facial dysmorphisms. Fewer than 30 cases have been reported to date. We conducted a case study and literature review; with clinical data obtained from medical records. A 2‐year‐old female presented with developmental delay, myoclonic epilepsy, hypotonia, and mild facial dysmorphism. Laboratory results showed elevated alkaline phosphatase (899 U/L) and low pyridoxal 5′‐phosphate levels in cerebrospinal fluid (CSF). Brain MRI revealed diffuse cerebral volume loss and ventriculomegaly. Trio genome sequencing identified two PIGV variants: c.1415T>C‐p.(Leu472Pro) and c.524T>C‐p.(Leu175Pro). Functional studies using PIGV ‐knockout HEK293 cells transfected with wild‐type or mutant PIGV constructs demonstrated reduced GPI‐anchored protein (GPI‐AP) expression under weaker promoters, indicating impaired enzymatic activity. We report two novel PIGV variants associated with HPMRS1, emphasizing the value of functional assays in variant interpretation. Our findings also highlight the diagnostic relevance of alkaline phosphatase measurement in patients with refractory seizures.

Abstract Twenty percent of patients with follicular lymphoma relapse early with poor outcomes; however, the molecular mechanisms underlying this aggressive behavior are unknown. Using a multiomic approach, we show that patients with follicular lymphoma with elevated IRF4 expression (IRF4hi) have increased transformation risk, dysregulated immune signaling, and a suppressive tumor microenvironment. Loss- and gain-of-function experiments in IRF4hi lymphoma cells, along with chromatin profiling, demonstrate that IRF4 impairs their interaction with T cells by repressing antigen presentation and co-receptor gene modules while promoting the expression of cytokines that antagonize T-follicular helper cell and regulatory T-cell functions. Additionally, IRF4 rewires tumor metabolism and restricts glucose availability to immune cells. Silencing of IRF4 inhibits tumor cell growth and restores immune surveillance mechanisms, thus representing a promising target for therapy. Our data suggest that IRF4hi lymphoma cells co-opt a developmental mechanism used to exit the germinal center response in promoting a more aggressive cancer via engagement of multiple immune-evasive mechanisms. Significance: We show that IRF4 controls immune and metabolic signaling with functional effects on the cross-talk between B and T cells, resulting in a suppressive immune microenvironment when IRF4 is overexpressed in lymphoma. This underscores the importance of IRF4 as a pivotal therapeutic target to restore antitumor immunosurveillance for IRF4-associated lymphomas.